Published Online
on March 28, 2005

A more recent version of this article appeared on April 5, 2005

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Submitted on June 15, 2004
Revised on December 13, 2004
Accepted on December 17, 2004

Thrombosis Modulates Arterial Drug Distribution for Drug-Eluting Stents

Chao-Wei Hwang MD, PhD^*, Andrew D. Levin MS, Michael Jonas MD, Pamela H. Li BS, and Elazer R. Edelman MD, PhD

From Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge (C.H., A.D.L., M.J., P.H.L., E.R.E.); and Department of Medicine (C.H.) and Cardiovascular Division, Department of Medicine (M.J., E.R.E.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.

^* To whom correspondence should be addressed. E-mail: cwhwang{at}post.harvard.edu.

Background--Drug-eluting stents deliver potent compounds directly to arterial segments but can become clot laden when deployed. The question arises as to whether thrombi affect drug elution and arterial uptake.

Methods and Results--Paclitaxel transport and retention were assessed in clots of different blood components. Diffusivity, affected by clot organization, is fastest in fibrin (347 µm²/s), slower in fibrin-red blood cell clots (34.98 µm²/s), and slowest in whole-blood clots (3.55 µm²/s). Blood cells bind and retain paclitaxel such that levels in clot increase linearly with red cell fraction. At physiological hematocrit, clot retains 3 times the amount of paclitaxel in surrounding solutions. Computational models predict that the potential of thrombus to absorb, retain, and release drug or to act as a barrier to drug delivery depends on clot geometry and strut position in clot relative to the vessel wall. Clot between artery and stent can reduce uptake 10-fold, whereas clot overlying the stent can shield drug from washout, increasing uptake. Model assumptions were confirmed and predictions were validated in a novel rat model that introduces thrombosis within stented aortas where nonocclusive thrombus acts as capacitive space for drug and shifts drug levels to decrease tissue uptake 2-fold.

Conclusions--Thrombus apposed on stents creates large variations in drug uptake and can act to either increase or decrease wall deposition according to the clot and stent geometry. Arterial deposition of drug from stents deployed in clots will be highly variable and unpredictable unless the clot can be adequately controlled or removed.

Key words: stents • thrombus • thrombosis • drugs • restenosis

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